Familial Alzheimer’s Disease‐linked Swedish mutation impairs APP axonal transport

Abstract

AbstractBackgroundIt is well‐established that most familial Alzheimer’s disease (AD) mutations alter processing of the amyloid precursor protein (APP) and perturb the balance between its proteolytic fragments. Considering different APP fragments play a role in its axonal transport, we here ask whether familial APP mutations impair axonal transport and homeostasis.MethodStem cells‐derived human neurons were transduced with either APPwt_GFP or APPswe_tRFP. Time‐lapse movies were analyzed using tracking algorithms to describe axonal transport parameters. Immunocytochemistry was performed to assess APP localization. To evaluate the impact of APPswe on other cargoes we also studied axonal transport of Rab5 endosomes.ResultProportions of movement, velocity, and distances of APPswe particles were decreased in anterograde direction compared to wt, while increased pauses and reversions were found. Accumulation of APP at the soma compared to neurite was found for APP mutant vs wt. Moreover, effect of APPswe resulted in the enlargement of Rab5 endosomes vs ctrl. Furthermore, to validate other effects of the APP mutant on Rab5, we studied its transport and found changes in some parameters compared with the ctrl.ConclusionThis work shows that APPswe impairs axonal transport. The change found on anterograde transport of APPswe, goes in hand with its accumulation at the soma vs neurite. Moreover, our results suggest that the Swedish mutation affects other proteins linked with APP, as described for the early‐endosome protein, Rab5. In line with many studies conducted on APP, our data suggest once more the importance of understanding as many mechanisms as possible involved in the biology of this protein.